The present invention relates to a series of new azetidinone derivatives, which are of value as intermediates in the preparation of certain carbapenem derivatives, many of which have valuable antibiotic properties. The invention also provides processes for the preparation of such azetidinone and carbapenem derivatives.
The carbapenems are a group of .beta.-lactam compounds characterised by the basic structure (A): ##STR2## This structure is known as "carbapenem" and forms the basis for the generally accepted semi-systematic nomenclature of carbapenem derivatives, which system is used herein.
Although many carbapenem derivatives have, in recent years, been proposed for use as antibiotics, many of them suffer from a problem which is common in the pharmaceutical industry: namely, preparation of these compounds is difficult or can be carried out only with low yields. There can be many reasons why these problems arise, for example starting materials may be difficult or even impossible to prepare on a commercial basis or may be obtainable only on a restricted basis or at high cost; alternatively, by the time the many process steps normally needed to produce carbapenem compounds have been carried out, the overall yield may be so small as to render the process uneconomic,
In copending U.S. patent application Ser. No. 407,914 filed 13th Aug. 1982, a series of carbapenem derivatives having excellent antibiotic activity has been disclosed and a process for producing such compounds is also disclosed.
Another process which can be used for preparing compounds of the type disclosed in the aforementioned U.S. patent application is disclosed in European Patent Specification No. 58317. The Process disclosed in this European Patent Specification includes reacting a compound of formula (B): ##STR3## (in which: R.sup.a represents a hydrogen atom, an alkyl group, an acylamino group or a substituted alkyl group; R.sup.b can represent a variety of organic groups, including alkyl and aryl groups, which may be substituted or unsubstituted; R.sup.c represents, inter alia, a carboxyl group or an esterified carboxyl group; Z represents, inter alia, a sulphur or oxygen atom; and X represents a sulphur or oxygen atom or a methylene group) with a trialkyl phosphite at a temperature within the range from 20.degree. to 80.degree. C. It has been reported by Afonso et al. J. Am. Chem. Soc., 104, 6138 (1982)! that the conditions under which this reaction is carried out are highly critical as the reaction of these two compounds can give rise to a phosphoranylidene derivative of formula (C): ##STR4## (in which R.sup.a, R.sup.b, R.sup.c, X and Z are as defined above and R.sup.d represents an alkoxy group). This phosphoranylidene derivative will not undergo cyclisation to give a penem or carbapenem compound and thus represents a wasted by-product.
It has also been reported by Ponsford et al. (J.C.S. Chem. Comm., 1979, 847), Oida et al. Chem. Pharm. Bull., 28, 3494 (1980)! and Kametani et al. (J.C.S. Perkin I, 1981, 964) that it is extremely difficult to undertake an intramolecular Wittig reaction with compounds of formula (C), but in which the sulphur atom has been replaced by an oxygen atom, and X is a methylene group, Z is a sulphur atom and R.sup.d is a phenyl group. Indeed, in the process disclosed in the aforementioned European Patent Application, one method of preparing the starting material of formula (B) includes a step in which a carbonyl oxygen atom is replaced by a sulphur atom (see, for example, Preparations R. S, T and U).
We have now discovered that compounds similar to those of formula (B) in which X represents a methylene group and R.sup.b represents a certain limited range of substituents, but in which the sulphur atom has been replaced by an oxygen atom, can be reacted with a limited class of phosphites and phosphorus amides, to give novel compounds similar to those of formula (C) and that surprisingly these novel compounds can readily be cyclised to give various carbapenem derivatives, many of which are of considerable interest as antibiotics. Certain of the carbapenem derivatives thus prepared are disclosed in copending U.S. patent application Ser. No. 407,914. filed 13th Aug. 1982.